Atherosclerotic Plaque Rupture Research Articles

Comparison of Different Intensive Lipid-Lowering Therapies for Patients with Acute Coronary Syndrome: Ezetimibe and Rosuvastatin Versus High-Dose Rosuvastatin

Introduction: Dyslipidaemias is a risk factor for atherosclerosis that leads to unstable atherosclerotic plaque rupture and acute coronary syndrome. Therefore, it is crucial to find a better control of risk factors to prevent the occurrence of a new acute cardiovascular event. Study aims: We aim to determine whether combining ezetimibe with a high-intensity statin would be a more effective and safer alternative therapy compared to high-intensity statin monotherapy for patients with coronary atherosclerotic heart disease. Materiel and methods: 65 patients were randomly assigned to high-intensity rosuvastatin (group 1) (rosuvastatin 20 mg/d, n = 33), or a combination therapy (group 2) (ezetimibe 10 mg/d and rosuvastatin 10 mg/d, n = 32) with a 3 month of follow-up. A lipid and general blood test to assess effectiveness and safety is done in 3 weeks and 3 months. Informed consent from patients is obtained before they participate in the study. Results: The primary endpoint was the proportion of patients who achieved the LDL-C goal of 55mg/dL in the third month: 60% in the second group vs. 33% in the first group, with a statistically significant difference (p=0.001). It was noted that there was a decrease in high-sensitivity C-reactive protein (Crp) without an increase in blood transaminases. Discussion and conclusion: Statin combined with ezetimibe demonstrates significant benefits in lowering LDL-C and preventing cardiovascular as statin high dose in acute coronary syndromes. Our results are consistent with the literature.

N-Terminal Proteomics Reveals Distinct Protein Degradation Patterns in Different Types of Human Atherosclerotic Plaques.

Atherosclerotic plaque rupture is a major cause of cardiovascular events. Plaque destabilization is associated with extracellular matrix (ECM) modification involving proteases which generate protein fragments with new N-termini. We hypothesized that rupture-prone plaques would contain elevated fragment levels, and their sequences would allow identification of active proteases and target proteins. Plaques from 21 patients who underwent surgery for symptomatic carotid artery stenosis were examined in an observational/cross-sectional study. Plaques were analyzed by liquid chromatography-mass spectrometry for the presence of N-terminal fragments. 33920 peptides were identified, with 17814 being N-terminal species. 5735 distinct N-terminal peptides were quantified and subjected to multidimensional scaling analysis and consensus clustering. These analyses indicated three clusters, which correlate with gross macroscopic plaque morphology (soft/mixed/hard), ultrasound classification (echolucent/echogenic), and the presence of hemorrhage/ulceration. Differences in the fragment complements are consistent with plaque-type-dependent turnover and degradation pathways. Identified peptides include signal and pro-peptides from synthesis and those from protein fragmentation. Sequence analysis indicates that targeted proteins include ECM species and responsible proteases (meprins, cathepsins, matrix metalloproteinases, elastase, and kallikreins). This study provides a large data set of peptide fragments and proteases present in plaques of differing stability. These species may have potential as biomarkers for improved atherosclerosis risk profiling.

TEAD1-Mediated Trans-Differentiation of Vascular Smooth Muscle Cells into Fibroblast-Like Cells Contributes to the Stabilization and Repair of Disrupted Atherosclerotic Plaques.

Atherosclerotic plaque rupture mainly contributes to acute coronary syndrome (ACS). Insufficient repair of these plaques leads to thrombosis and subsequent ACS. Central to this process is the modulation of vascular smooth muscle cells (VSMCs) phenotypes, emphasizing their pivotal role in atherosclerotic plaque stability and healing post-disruption. Here, an expansion of FSP1+ cells in a tandem stenosis (TS) model of atherosclerotic mice is unveiled, predominantly originating from VSMCs through single-cell RNA sequencing (scRNA-seq) analyses and VSMC lineage tracing studies. Further investigation identified TEA domain transcription factor 1 (TEAD1) as the key transcription factor driving the trans-differentiation of VSMCs into fibroblast-like cells. In vivo experiments using a TS model of plaque rupture demonstrated that TEAD1 played a crucial role in promoting plaque stability and healing post-rupture through pharmacological or TEAD1-AAV treatments. Mechanistically, it is found that TEAD1 promoted the expression of fibroblast markers through the Wnt4/β-Catenin pathway, facilitating the trans-differentiation. Thus, this study illustrated that TEAD1 played a critical role in promoting the trans-differentiation of VSMCs into fibroblast-like cells and subsequent extracellular matrix production through the Wnt4/β-Catenin pathway. Consequently, this process enhanced the healing mechanisms following plaque rupture, elucidating potential therapeutic avenues for managing atherosclerotic instability.

Type 2 myocardial infarction: challenges in diagnosis and treatment.

The Fourth Universal Definition of Myocardial Infarction recommends a classification based on aetiology, in recognition that the underlying pathophysiology of myocardial infarction influences the approach to investigation and treatment. Type 1 myocardial infarction occurs due to atherosclerotic plaque rupture with thrombosis, whereas type 2 myocardial infarction occurs due to an imbalance in myocardial oxygen supply or unmet need in myocardial oxygen demand, without atherothrombosis, usually in the context of another acute illness. In this state-of-the-art review, the diagnosis, investigation, and treatment of patients with type 2 myocardial infarction are considered, with general advice for clinical practice and a consideration of future research directions.

NIR-II Imaging for Tracking the Spatiotemporal Immune Microenvironment in Atherosclerotic Plaques.

The inflammatory immune microenvironment is responsible for atherosclerotic plaque erosion and rupture. Near-infrared-II (NIR-II) fluorescence imaging has the potential to continuously monitor the spatiotemporal changes in the plaque immune microenvironment. Herein, we constructed three different NIR-II probes based on benzo[1,2-c;4,5-c']bis[1,2,5]thiadiazole-4,7-bis(9,9-dioctyl-9H-fluoren-2-yl)thiophene (denoted as BBT-2FT): VHPK/BBT-2FT NPs, where VHPK is a specific peptide targeting vascular cell adhesion molecule-1; iNOS/BBT-2FT NPs for modulating the polarization of M1 macrophages by inducible NO synthase (iNOS) antibodies; and Arg-1/BBT-2FT for counterbalancing the inflammatory responses of M1 macrophages. These tracers enable precise tracking of atherosclerotic plaques and M1 and M2 macrophages through NIR-II imaging. VHPK/BBT-2FT NPs can accurately trace atherosclerotic plaques at various stages. Arg-1/BBT-2FT NPs precisely located M2 macrophages in the early plaque microenvironment with upregulation of peroxisome proliferator-activated receptor γ (PPAR-γ), signal transducer and activator of transcription (STAT) 6, and ATP-binding cassette transporter A1 (ABCA1), indicating that M2 macrophage polarization is crucial for early plaque lipid clearance. Meanwhile, iNOS/BBT-2FT NPs accurately tracked M1 macrophages in the advanced plaque microenvironment. The results showed that M1 macrophage polarization induces the formation of an inflammatory microenvironment through anaerobic glycolytic metabolism and pyroptosis in the advanced hypoxic plaque microenvironment, as indicated by the upregulation of hypoxia-inducible factor 1 alpha (HIF-1α), STAT1, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), pyruvate dehydrogenase kinase 1 (PDK1), and glucose transporter 1 (GLUT-1). Combining immunological approaches with NIR-II imaging has revealed that hypoxia-induced metabolic reprogramming of macrophages is a key factor in dynamic changes in the immune microenvironment of atherosclerotic plaques. Furthermore, our strategy shows the potential for real-time diagnosis and clinical prevention of unstable plaque rupture in atherosclerosis.

Emerging nanoprobes for the features visualization of vulnerable atherosclerotic plaques.

Atherosclerosis (AS) is a major cause of cardiovascular disease. In particular, the unpredictable rupture of vulnerable atherosclerotic plaques (VASPs) can cause serious cardiovascular events such as myocardial infarction, stroke, and even sudden death. Therefore, early evaluation of the vulnerability of atherosclerotic plaques is of great importance. However, clinical imaging techniques are only marginally useful in the presence of severe anatomical structural changes, making it difficult to evaluate plaque vulnerability at an early stage. With the development of molecular imaging and nanotechnology, specific nanoprobes constructed for the pathological features of VASPs have attracted much attention for their ability to visualize VASPs early and noninvasively at the cellular and molecular levels. Here, we outline the pathological features of VASPs, analyze the superiority and limitations of current clinical imaging techniques, introduce the rational design principles of nanoprobes, and systematically summarize the application of nanoprobes to visualize the features of VASPs at the cellular and molecular levels. In addition, we discussed the prospects and urgent challenges in this field, and we believe it will provide new ideas for the early and accurate diagnosis of cardiovascular diseases.

Platelet-Leukocyte Aggregate and Interleukin-6: An Emerging Perspective on a New Diagnostic and Therapeutic Clue for Acute Coronary Syndrome, A Case-Control Study.

Acute coronary syndrome (ACS) is one of the most important cardiovascular diseases. The rupture of atherosclerotic plaques in coronary arteries is considered the underlying pathophysiology of ACS. The interaction between cytokines and leukocytes in the presence of platelets results in platelet-leukocyte aggregate (PLA). Monocytes, neutrophils, and cytokines are prime factors that promote PLA formation, which leads to atherosclerotic plaque progression and subsequent ACS development. This study aimed to investigate PLA (PMA and PNA) formation and cytokine (IL-6 and TNF-α) levels as well as the correlation between them in ACS patient samples to identify diagnostic markers. A total of 30 patients with ACS and 24 healthy controls participated in this study. Flow cytometry analysis was performed to evaluate PLA formation, and the serum levels of cytokines were assessed by ELISA. The Pearson's correlation coefficient and ROC curve were calculated to investigate the correlation between the parameters and their diagnostic value, respectively. The results showed that PMA, PNA, and IL-6 levels were significantly higher in ACS patients than in healthy controls. Additionally, TNF-α levels were not significantly increased in the patient group. In addition, the Pearson's correlation coefficient results revealed a direct linear and statistically significant relationship between PMA-IL-6 and PNA-IL-6 as well as a direct linear but statistically nonsignificant relationship between IL-6-TNF-α and PMA-PNA, whereas a convers linear but nonsignificant correlation was shown between PMA and TNF-α and no correlation was detected between PNA and TNF-α. Finally, ROC curve analysis revealed that the PMA, PNA, and IL-6 can have diagnostic value. In conclusion, the PMA, PNA, and IL-6 can be used as powerful diagnostic markers in ACS patients. Therefore, disrupting PMA and PNA formation and inhibiting cytokine production may be new strategies for the treatment of ACS. However, further investigations are required to explore these parameters in the clinical diagnosis of ACS.

The influence between plaque rupture and non-plaque rupture on clinical outcomes in patients with ST-segment elevation myocardial infarction after primary percutaneous coronary intervention: a prospective cohort study.

Coronary atherosclerosis can lead to acute clinical events upon atherosclerotic plaque rupture (PR) or erosion and arterial thrombus formation. Identifying the effect of distinct plaque characteristics on clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) is critical for clinical therapy. Our goal was to ascertain the correlation between clinical outcome, long-term prognosis, and morphological plaque characteristics in STEMI. The data used in this prospective cohort research came from a prior multicenter prospective cohort study (ChiCTR1800019923). One hundred and thirteen consecutive STEMI patients were involved in our cohort study. Patients with STEMI who received primary percutaneous coronary intervention (pPCI) within 24 hours of symptom onset were included in the study and divided into two groups according to plaque characteristics derived from intravascular ultrasound (IVUS): a PR group and a non-PR group. The primary outcome was the incidence of no reflow or slow flow, the secondary outcome was major adverse cardiac events (MACEs) at 1-year follow-up. This study enrolled 113 consecutive patients with STEMI [mean age 56 (range, 49-65.5) years; males 90.27%]. Of the 113 patients, PR was found in 93 (82.3%), while non-PR was found in 20 (17.7%). The PR group had a higher rates of plaque eccentricity index (64.28%±22.69% vs. 60.08%±15.54%; P=0.045), higher rates of lipid pool-like images (62.37% vs. 30.00%; P=0.008), and higher rates of tissue prolapse (22.95% vs. 13.33%; P=0.01). Compared with that in the non-PR group, the incidence of no reflow or slow flow was higher in the PR group after pPCI (26.88% vs. 5.00%; P=0.04). Multivariable logistic regression showed that PR [odds ratio (OR) =8.188; 95% confidence interval (CI): 1.020-65.734; P=0.048] was an independent predictor of no reflow or slow flow. Survival analysis revealed no significant differences in MACE incidence between the two groups at 1-year follow-up (7.61% vs. 10.00%; P=0.66). Furthermore, 29 patients with PR were treated without stenting, most of them were free of MACEs (27/29). MACE between subgroups of stenting and non-stenting had no significant differences (7.94% vs. 6.90%; P=0.86) in the PR group. In comparison to patients with non-PR, PR were not associated with the risk of recurrent myocardial infarction (MI), revascularization, heart failure, or cardiac death at 1-year follow-up, while associated with an increased incidence of no reflow or slow flow during pPCI. This observation would be considered while risk stratification and dealing with patients who have STEMI. Most patients with PR who were treated without stenting were MACE free. Further research should be conducted to determine whether interventional treatment without stenting is feasible for patients with STEMI and PR.

The Role of Platelets in Atherosclerosis: A Historical Review.

Atherosclerosis is a chronic, multifactorial inflammatory disorder of large and medium-size arteries, which is the leading cause of cardiovascular mortality and morbidity worldwide. Although platelets in cardiovascular disease have mainly been studied for their crucial role in the thrombotic event triggered by atherosclerotic plaque rupture, over the last two decades it has become clear that platelets participate also in the development of atherosclerosis, owing to their ability to interact with the damaged arterial wall and with leukocytes. Platelets participate in all phases of atherogenesis, from the initial functional damage to endothelial cells to plaque unstabilization. Platelets deposit at atherosclerosis predilection sites before the appearance of manifest lesions to the endothelium and contribute to induce endothelial dysfunction, thus supporting leukocyte adhesion to the vessel wall. In particular, platelets release matrix metalloproteinases, which interact with protease-activated receptor 1 on endothelial cells triggering adhesion molecule expression. Moreover, P-selectin and glycoprotein Ibα expressed on the surface of vessel wall-adhering platelets bind PSGL-1 and β2 integrins on leukocytes, favoring their arrest and transendothelial migration. Platelet-leukocyte interactions promote the formation of radical oxygen species which are strongly involved in the lipid peroxidation associated with atherosclerosis. Platelets themselves actively migrate through the endothelium toward the plaque core where they release chemokines that modify the microenvironment by modulating the function of other inflammatory cells, such as macrophages. While current antiplatelet agents seem unable to prevent the contribution of platelets to atherogenesis, the inhibition of platelet secretion, of the release of MMPs, and of some specific pathways of platelet adhesion to the vessel wall may represent promising future strategies for the prevention of atheroprogression.

Abstract 4132291: Assessing the Efficacy of Preventive Percutaneous Coronary Intervention vs Optimal Medical Therapy for the Treatment of Vulnerable Plaque: A Meta-analysis

Introduction: Rupture and thrombosis of lipid-rich atherosclerotic plaques (vulnerable plaques) contributes to majority of acute coronary syndrome (ACS). Current guidelines recommend optimal medical therapy (OMT) for stabilization of vulnerable plaques. Recent evidence of preventive percutaneous intervention (PCI) as a targeted treatment shows improvement in outcomes in these patients. Hypothesis/Goals/Aims: We aim to evaluate the efficacy of preventive percutaneous coronary intervention (PCI) compared to optimal medical therapy (OMT) for treatment of non-vulnerable plaque within five years of follow up from available selected randomized controlled trials (RCTs). Methods: PubMed, Cochrane, OVID, and NIH Clinical Trials were searched for RCTs evaluating preventive PCI compared to standard of care medical therapy. All trials reported primary common endpoints as death from cardiac cause and myocardial infarction (MI). Secondary outcomes included all-cause mortality, any revascularization, hospitalization for unstable and progressive angina, and composite death (any cause, MI, or any revascularization). Sub analyses for secondary outcomes were included if measured by RCT. A fixed effect model with Mantel-Haenszel statistical method was used to calculate risk ratios, Z scores, and a 95% confidence interval. Results: Ten RCTs (n=15955 patients) were included. Preventive PCI of vulnerable plaques revealed a significant benefit in lowering incidence of MI (RR: 0.86 [0.77, 0.86], p=0.01) and death from cardiac cause (RR: 0.73 [0.62, 0.86], p=0.004). Similarly, patients undergoing preventive PCI had a lower incidence of hospitalization for unstable or progressive angina (RR: 0.75 [0.62, 0.91], p<0.0001) and composite death (RR: 0.55 [0.46, 0.67], p<0.001). No difference was noted in all-cause mortality. Incidence of revascularization had a significant benefit with OMT therapy compared to preventive PCI (RR: 1.84 [1.75, 1.94], p<0.0001). Conclusion: Preventive PCI in vulnerable plaque demonstrates cardiovascular benefit as a result from lower incidence of MI, death from cardiac cause, composite death and fewer hospitalization for unstable or progressive angina.

Teriparatide administration is osteoanabolic but does not impact atherosclerotic plaque calcification and progression in a mouse model of menopause

Menopause exacerbates osteoporosis and increases the risk of atherosclerotic plaque rupture, leading to cardiovascular mortality. Osteoporotic women are increasingly treated with teriparatide (TPTD, 1–34 parathyroid hormone), one of the few treatments that stimulate bone formation. Despite the fact that atherosclerotic plaque calcification is a hallmark of plaque development, the impact of TPTD administration on plaque calcification remain unclear. In this context, we sought to determine the effects of TPTD administration on atherosclerosis in ovariectomized (OVX) apolipoprotein E deficient mice (ApoE−/−), as a model of postmenopausal osteoporosis. OVX ApoE−/− mice, fed a high fat, high cholesterol diet to induce atherosclerosis, received either vehicle or TPTD daily injections (40 μg/kg/d) for 4 or 10 weeks, at which points plaques are respectively weakly and heavily calcified. After sacrifice, bone remodeling was evaluated by serum markers and bone histomorphometry. Bone architectural parameters were measured by μCT. Aortic plaques were analyzed histologically, and their calcification with von Kossa staining and the calcium tracer Osteosense. Plaque inflammation and calcification markers were measured by RT-qPCR. Intermittent TPTD increased bone volume in OVX mice, due to a higher stimulation of bone formation relatively to bone resorption. These effects were not accompanied by changes in serum levels of cholesterol, triglycerides, glucose or insulin. TPTD neither significantly affected aortic plaque size, inflammation, and calcification, even if it slightly increased vascular smooth muscle cell transdifferentiation into calcifying cells. In conclusion, TPTD exhibits osteoanabolic effects in OVX ApoE−/− mice, without significantly influencing atherosclerotic plaque progression or calcification in the short term.

Deep Learning and Single-Cell Sequencing Analyses Unveiling Key Molecular Features in the Progression of Carotid Atherosclerotic Plaque.

Rupture of advanced carotid atherosclerotic plaques increases the risk of ischaemic stroke, which has significant global morbidity and mortality rates. However, the specific characteristics of immune cells with dysregulated function and proven biomarkers for the diagnosis of atherosclerotic plaque progression remain poorly characterised. Our study elucidated the role of immune cells and explored diagnostic biomarkers in advanced plaque progression using single-cell RNA sequencing and high-dimensional weighted gene co-expression network analysis. We identified a subcluster of monocytes with significantly increased infiltration in the advanced plaques. Based on the monocyte signature and machine-learning approaches, we accurately distinguished advanced plaques from early plaques, with an area under the curve (AUC) of 0.899 in independent external testing. Using microenvironment cell populations (MCP) counter and non-negative matrix factorisation, we determined the association between monocyte signatures and immune cell infiltration as well as the heterogeneity of the patient. Finally, we constructed a convolutional neural network deep learning model based on gene-immune correlation, which achieved an AUC of 0.933, a sensitivity of 92.3%, and a specificity of 87.5% in independent external testing for diagnosing advanced plaques. Our findings on unique subpopulations of monocytes that contribute to carotid plaque progression are crucial for the development of diagnostic tools for clinical diseases.

Localization of Hemostasis Elements in Aspirated Coronary Thrombi at Different Stages of Evolution.

The structure of aspirated coronary thrombus in ST-segment elevation myocardial infarction (STEMI) is still being studied. Our aims were to characterize coronary thrombi of different ages, focusing on the appearance of activated protein C (APC/PC) and its relation to the elements of neutrophil extracellular traps (NETs), and the factors closely related to fibrin as factor XIII (FXIII) and α2 plasmin inhibitor (α2-PI). The thrombi of n = 24 male patients with atherosclerotic coronary plaque rupture related to native coronary artery occlusion were selected for histopathology analysis. Thrombus age was distinguished as fresh, lytic, and organized, and then analyzed by immunofluorescent staining and confocal microscopy. FXIII was present at a high level and showed a high degree of co-localization with fibrin in all stages of thrombus evolution. The amount of α2-PI was low in the fresh thrombi, which increased significantly to the lytic phase. It was evenly distributed and consistently associated with fibrin. APC/PC appeared in the fresh thrombus and remained constant during its evolution. The presence of NET marker and CD66b was most dominant in the lytic phase. APC/PC co-localization with the elements of NET formation shows its role in NET degradation. These observations suggest the importance of searching for further targeted therapeutic strategies in STEMI patients.

Deficiency of transcription factor E4BP4 suppresses neointimal formation after vascular injury

Abstract Aim In addition to traditional risk factors such as hypertension, diabetes, and dyslipidemia, chronic inflammation is deeply involved in the onset and pathogenesis of atherosclerotic diseases. Furthermore, diurnal fluctuations are observed in the rupture of atherosclerotic plaques and the onset of myocardial infarction. There are still many patients for whom medical treatments such as statins and antihypertensive drugs do not respond adequately, and new treatment methods are expected. E4BP4 (also known as NFIL3) is a basic leucine zipper (bZIP)-type transcription factor associated with circadian rhythms and cell viability, and it has been reported that E4BP4 regulates inflammation. Therefore, to investigate how the circadian transcription factor E4BP4 which is involved in inflammation, we decided to examine the role of E4BP4 in neointimal formation after vascular injury. Methods and Results Using E4BP4-deficient (E4BP4−/−) and wild-type (WT) mice, we investigated neointimal formation 2 weeks after femoral artery injury induced by an external vascular cuff model. Intimal and medial area were measured, and the intima/media ratio was calculated. Systolic blood pressure was similar between groups (WT mice: 92 ± 5 mmHg [n = 5] vs. E4BP4−/− mice: 90 ± 4 mmHg [n = 5]). And there was no significant difference in baseline body weight between groups (WT mice: 22.4 ± 0.8 g [n = 5] vs. E4BP4−/− mice: 22.0 ± 1.1 g [n = 5]). The mean intimal area and the intima/media ratio of E4BP4−/− mice decreased by 86 % (WT mice: 3,683 ± 512 μm2 [n = 10] vs. E4BP4−/− mice: 521 ± 363 μm2 [n = 10]; P < 0.0001) and 97% (WT mice: 0.33 ± 0.05 vs. E4BP4−/− mice: 0.01 ± 0.03; P < 0.0001), compared with WT mice. However, we observed no significant difference in the medial area (WT mice: 11,019 ± 358 μm2 vs. E4BP4−/− mice: 11,281 ± 401 μm2; P = NS) between groups (Figure). Immunohistochemistry for NK cell (NKp46) revealed the percentage of NKp46 positive area in the adventitia of E4BP4−/− mice was significantly lower compared with WT mice at 14 days post-injury (P <0.05). Furthermore, the positive area of IL-6 (P<0.05), TNF-α (P<0.05) and IFN-γ (P<0.05) in the intima of E4BP4−/− mice tended to be much smaller than those of WT mice. Our findings indicate that E4BP4 might induce vascular inflammation following vascular injury. Conclusions Deficiency of E4BP4 reduced the inflammatory cytokines and suppressed neointimal formation after injury. We also observed a decrease in NKp46, suggesting that NK cell development is impaired by E4BP4 deficiency. The present study is the first to demonstrate that E4BP4 plays an important role in the increase of neointimal formation after injury in vivo, thus suggesting that E4BP4 inhibition may represent a useful strategy to inhibit vascular inflammation.Neointimal formation after cuff injury

High physical activity relates to higher risk of incident carotid plaque components

Abstract Background The rupture of carotid atherosclerotic plaque, primarily driven by plaque components, is among the leading causes of ischemic stroke. Although physical activity (PA) stands as a major modifiable target for prevention of atherosclerotic diseases, recent studies suggested a potential adverse impact of high-volume PA on atherosclerotic plaque burden in athletes. Data remains scarce from the community-dwelling population regarding to the impact of PA on the longitudinal change of carotid plaque components. Objectives To assess the association between PA and the incidence of carotid plaque components and explore whether the association of PA with stroke and all-cause mortality differs by the presence of plaque components. Methods Between 2007 and 2012, in a community- dwelling cohort in Netherlands, 1327 stroke-free persons (mean ± standard deviation age 72 ± 9 years, 45% women) with carotid atherosclerosis (carotid intima-media thickness > 2.5 mm) were invited for magnetic resonance imaging (MRI) to assess carotid plaque components. From these, 696 persons (1267 carotid arteries) underwent a follow-up MRI between 2014 and 2017 (median between-scan interval 6 years). Carotid plaque components included calcification, intraplaque hemorrhage (IPH), and lipid-rich necrotic core (LRNC). The volume of moderate, vigorous and total PA (unit: metabolic equivalent task hour, MET-h) was assessed using LASA Physical Activity Questionnaires around the time of the first MRI scan. Participants were followed for the occurrence of stroke or all-cause mortality until December 31, 2019. Generalized estimation equation and Cox regression models were used in the analyses, with adjustments for plaque size and other cardiovascular risk factors. Results Compared to lowest quintile PA group, participants in the highest quintile total PA group had a higher risk of new onset of plaque components, odds ratio (95%CI) 2.69 (1.21; 5.94) for calcification, 1.35 (0.82; 2.24) for LRNC and 1.93 (1.12; 3.34) for IPH (Figure 1). Similar associations were observed for vigorous PA but not for moderate PA. Over a median follow-up of 9.5 years, 118 persons suffered a stroke and 298 died. As shown in table 1, baseline IPH, rather than LRNC or calcification, modulated the associations of PA with stroke and all-cause mortality (P-interaction <0.05): higher total PA was associated with a lower risk of stroke among IPH-free persons, with the hazard ratio (95% CI) of 0.929 (0.867; 0.996) per 10 MET-h/week increase; no associations between PA and stroke were found among those with IPH. Similar associations were found between vigorous PA and all-cause mortality. Conclusions Among the middle-aged and elderly with subclinical atherosclerosis, high level PA, especially high vigorous PA, may lead to an unstable carotid plaque. The beneficial effect of PA on stroke and all-cause mortality is only among persons with a stable carotid plaque profile, especially without IPH.

The evolution of carotid atherosclerotic plaque composition: a prospective study

Abstract Background The rupture of carotid atherosclerotic plaque is one of the major causes of ischemic stroke, and largely determined by the composition of the plaque. To date, most studies on carotid plaque composition focused on individual plaque components, whilst the interplay between different components within the same plaque may be a critical driving force for plaque evolution and rupture. Objectives To determine the interplay between carotid plaque components over time and describe the dynamics of plaque composition with a specific focus on age- and sex-specific changes in a population-based setting. Methods From a population-based cohort in Netherlands, 802 participants (mean age ± SD 68 ± 8 years, 43% women) with subclinical carotid atherosclerosis underwent repeat magnetic resonance imaging (MRI) of carotid plaque (first scan between 2007 and 2012, second scan between 2014 to 2017). We evaluated carotid plaque composition, including calcification, lipid-rich necrotic core (LRNC) and intraplaque hemorrhage (IPH). To assess the relationship between the incidence of one specific component and baseline plaque composition, plaques with this specific component present at the baseline were excluded. Generalized estimation equation models were used with adjustments for baseline plaque size and cardiovascular risk factors. We demonstrated the evolution of plaque composition along age and by sex. Results Baseline presence of calcification in carotid plaque is independently associated with a higher incidence of IPH (adjusted odds ratio: 2.25; 95% confidence interval: 1.40 to 3.63). No associations were found between baseline plaque composition and the new onset of calcification or LRNC. The proportion of complex plaques with multiple components significantly increased at follow-up (Figure 1a). The plaque composition dramatically evolved over time and the proportion of plaques with two or more components started with 10% around 55 years and increased to over 50% after 70 years of age (Figure 1b). Although the age distribution was comparable between men and women, men were more likely to have and develop plaques with multiple vulnerable plaque components such as IPH (Figure 2). Conclusions A higher incidence of IPH was found in plaques with baseline calcification. The pre-existing plaque composition strongly determines how the plaque will evolve over time. Given the interplay between individual components, the overall plaque composition exhibits significant age- and sex- specific characteristics.

Antiplatelet can improve the short-term prognosis of type 2 myocardial infarction caused by acute respiratory failure

Abstract Background Type 2 myocardial infarction (T2MI) is characterized by myocardial infarction resulting from an imbalance between myocardial oxygen supply and demand, without the rupture of acute atherosclerotic plaque. Antiplatelet therapy is the cornerstone of treatment for Type 1 myocardial infarction, however, its efficacy in T2MI remains unclear. Purpose This study aimed to explore the impacts of antiplatelets on prognosis in patients with T2MI caused by acute respiratory failure. Methods The data for this study were derived from the Health and Medical Big Data Superplatform, comprising a retrospective cohort of patients admitted to and discharged from 72 secondary and tertiary hospitals from 2010 to 2023. A total of 4708 patients with T2MI due to acute respiratory failure were included. Participants were divided into two groups: those receiving antiplatelet therapy and those not. T2MI caused by acute respiratory failure was defined as NSTEMI patients caused by respiratory failure without percutaneous coronary intervention (PCI). Propensity score matching (PSM) was used to balance covariates between the groups, followed by building a multivariable Cox regression model to further adjust for potential confounders. Covariates adjusted in multivariable Cox regression included antiplatelet, anticoagulant, and lipid-lowering drug use during hospitalization, age, sex, KILLIP classification, history of diabetes, hypertension, percutaneous coronary intervention, stroke, renal insufficiency, cerebral hemorrhage, and atrial fibrillation. One-to-one matching was performed based on propensity scores using the nearest available pair matching method with a caliper width of 0.01. The primary endpoint was Net Adverse Clinical Events (NACE) within 1 month, including myocardial infarction, cardiac death, stroke and Bleeding Academic Research Consortium (BARC) criteria type 3 or 5. Results Following 1:1 propensity score matching, a total of 1418 participants were enrolled in the final study sample, with 709 patients retained in each group. Patients using antiplatelet were more likely to use ACEI/ARB, CCB, and β-blockers during hospitalization, all p<0.05.Compared to non-antiplatelet therapy group, the use of antiplatelet was associated with a 0.69 times risk of 1-month NACE (aHR, 0.69; p<0.001), a 0.69 times risk of 1-month Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) (aHR, 0.69; p<0.001), a 0.70 times risk of 1-month cardiac death (aHR, 0.70; p<0.001), and a 0.70 times risk of 1-month all-cause mortality (aHR, 0.70; p<0.001); with no statistical significance for other clinical outcomes (p > 0.05) (Figure 1). Conclusions The present study suggested that patients receiving antiplatelet therapy had a lower incidence of one-month NACE, primarily due to a reduction in major cardiac death and MACCE at 1 month.

Predictive models for cholesterol crystals and plaque vulnerability in acute myocardial infarction: Insights from an optical coherence tomography study

BackgroundCholesterol crystals (CCs) are recognized as a risk factor for vulnerable atherosclerotic plaque rupture (PR) and major adverse cardiovascular events. However, their predictive factors and association with plaque vulnerability in patients with acute myocardial infarction (AMI) remain insufficiently explored. Therefore, This study aims to investigate the association between CCs and plaque vulnerability in culprit lesions of AMI patients, identify the factors influencing CCs formation, and develop a predictive model for CCs. MethodsA total of 431 culprit lesions from AMI patients who underwent pre-intervention optical coherence tomography (OCT) imaging were analyzed. Patients were divided into groups based on the presence or absence of CCs and PR. The relationship between CCs and plaque vulnerability was evaluated. A risk nomogram for predicting CCs was developed using the least absolute shrinkage and selection operator and logistic regression analysis. ResultsCCs were identified in 64.5 % of patients with AMI. The presence of CCs was associated with a higher prevalence of vulnerable plaque features, such as thin-cap fibroatheroma (TCFA), PR, macrophage infiltration, neovascularization, calcification, and thrombus, compared to patients without CCs. The CCs model demonstrated an area under the curve (AUC) of 0.676 for predicting PR. Incorporating CCs into the TCFA model (AUC = 0.656) significantly enhanced predictive accuracy, with a net reclassification improvement index of 0.462 (95 % confidence interval [CI]: 0.263–0.661, p < 0.001) and an integrated discrimination improvement index of 0.031 (95 % CI: 0.013–0.048, p = 0.001). Multivariate regression analysis identified the atherogenic index of plasma (odds ratio [OR] = 2.417), TCFA (OR = 1.759), macrophage infiltration (OR = 3.863), neovascularization (OR = 2.697), calcification (OR = 1.860), and thrombus (OR = 2.430) as independent risk factors for CCs formation. The comprehensive model incorporating these factors exhibited reasonable discriminatory ability, with an AUC of 0.766 (95 % CI: 0.717–0.815) in the training set and 0.753 (95 % CI: 0.704–0.802) in the internal validation set, reflecting good calibration. Decision curve analysis suggested that the model has potential clinical utility within a threshold probability range of approximately 18 % to 85 %. ConclusionsCCs were associated with plaque vulnerability in the culprit lesions of AMI patients. Additionally, this study identified key factors influencing CCs formation and developed a predictive model with potential clinical applicability.

Biomechanics cerebral and carotid arteries: aneurysm development and atherosclerotic plaque detachment in the presence of combined pathologies

Today, the main cause of mortality in the world remains cardiovascular diseases. In this case, the combined pathology of the neck and head arteries, in which atherosclerosis affects the carotid arteries and there is a change in blood flow in the vertebral arteries or in the circle of Willis due to aplasia of the communicating artery, significantly increases the risk of aneurysms formation and their subsequent rupture. Assessing the risk of complications in this type of pathological condition may allow the physician to initiate timely preventive measures in specific clinical cases. The paper presents the results of modelling various variants of combined pathologies in the arteries of the neck and head. The segment under consideration includes sections of the common carotid, external and internal carotid arteries, as well as vessels of the circle of Willis and the basilar artery. The main idea of the study was to create a prognostic model to assess the risks of aneurysm formation in the circle of Willis and atherosclerotic plaque rupture in the carotid arteries. Such a system may be useful for physicians in routine practice when planning treatment tactics in patients with combined pathologies of the arterial channel. Based on the literature analysis, a number of pathologies of the cerebral and carotid arteries, most frequently occurring in various combinations, were identified: stenoses of the ICA (30 % and 70 %) and aplasia (absence) of one of the connecting arteries were considered from the point of view of geometrical features. In addition, the character of blood flow in the basilar artery, which can change its direction in steal-syndrome, was taken into account. Based on the analysis of blood flow and wall shear stress, two degrees of risk of aneurysm formation were distinguished. High risk corresponds to cases for which both of these values were statistically significantly different from the norm. Medium risk corresponds to cases for which only one of the values was statistically significantly different from the norm. For models containing atherosclerotic plaques, data on shear and normal stresses on the surfaces of atherosclerotic plaques were tabulated. The risk of plaque rupture on each side was determined for each case by analysing the result sets 11 combinations of pathological conditions with increased risk were indicated.

Neutrophil count as a risk factor for cardiovascular diseases: how can we manage it?

Neutrophils activation plays a pivotal role in the pathogenesis of atherosclerotic plaque formation, progression and rupture. An association between the leukocyte count and the risk of developing myocardial infarction has been well known for many years; however, only recently did Mendelian randomization studies show that a high neutrophil count is a causal risk factor for atherosclerotic cardiovascular disease. On the other hand, experimental studies show that depletion of circulating neutrophils impairs plaque development. Clopidogrel, an antiplatelet agent, is widely used in combination with aspirin to reduce the incidence of ischemic events in patients treated with coronary stenting. Chronic treatment with this drug reduces inflammatory markers and neutrophil numbers, rarely causing severe leukopenia. The purpose of this review is to present recent evidence showing the link between neutrophil number and the development of cardiovascular diseases and to discuss how the clopidogrel-induced reduction in the neutrophil count may be a beneficial off-target effect of this drug.